Many therapeutic substances that operate systemically are not suitable for the relative simplicity of oral dosing and must be administered parenterally instead. However, often the same factors that complicate oral dosing impede the parenteral dosing process. Such factors include poor water solubility due to hydrophobicity or other properties, drug instability in the digestive tract, insufficient absorption or enhanced clearance after absorption, resulting in inadequate plasma concentrations and/or exposure times.
Options for dealing with hydrophobic drugs requiring parenteral dosing usually involve the addition of various excipients to obtain stable suspensions, dispersions or solutions suitable for injection. The types of excipients used include detergents, polymers of various types, oil emulsions, phospholipids and albumin. In many cases the excipients used to obtain the necessary drug solubilization are detergent-like substances. These include deoxycholate; Cremophor EL®, a polyethyloxated derivative of castor oil; and polysorbate 80. The latter two are typically used in tandem with ethanol. These agents solve the solubilization problem but they have noxious properties which introduce a high risk of hypersensitivity reactions. It is a common requirement that patients injected with solutions containing Cremophore EL® or polysorbate 80 are pretreated with anti-inflammatory drugs to subdue formulation-dependent inflammation. The most serious consequences of hypersensitivity reactions are reduced tolerance to treatment and increased risk of death.
Examples of approved drug formulations containing Cremophore EL® or polysorbate 80 for solubilization include the hydrophobic anti-cancer drugs paclitaxel (Taxol®), docetaxel (Taxotere®), cabazitaxel (Jevtana®) and ixabepilone (Ixempra®). The immnuosuppresants cyclosporine (Sandimmune®), tacrolimus (Prograf®) and temsirolimus (Torisel®) also depend on these agents for formulation. In the case of paclitaxel, some progress has been made through the substitution of albumin for Cremophore EL® and ethanol as a dispersing agent (i.e. Abraxane®). The antifungal agent amphotericin B is also quite hydrophobic and requires measures to obtain a stable suspension for infusion.
Other dosing hurdles many drugs face include rapid clearance and inactivation by metabolic pathways. For example, the anti-cancer agent gemcitabine must be infused at high doses to overwhelm its breakdown by cytidine deaminase in order to obtain therapeutic levels. A further problem limiting drug administration is unintended exposure of non-target tissues to the effects of those drugs. This is particularly significant for cytotoxic anti-cancer drugs.
Descriptions of attempts to discover superior parenteral formulations including emulsions, micelles, liposomal formulations, polymers, and solid-lipid nanoparticles, are numerous but many efforts have been hindered by problems of low entrapment efficiency, drug instability, payload leakage and poor storage stability. Some success has been obtained with liposomal formulations. Examples include cytarabine in liposomes (DepoCyt®) to reduce clearance rates, doxorubicin in liposomes (Doxil®, Myocet®) to reduce cardiotoxicity, and amphotericin-B in liposomes (e.g. AmBisome®) to improve solubilization.
Given the limited number of current treatments, and inadequacy of options, there is a clear need to provide formulation alternatives for parenterally administered drugs with improved safety profiles and therapeutic indexes; and/or therapies which at least provide the public with a useful choice.